US2021379060A1PendingUtilityA1
Spt5 inhibitors and uses thereof
Est. expiryFeb 14, 2039(~12.5 yrs left)· nominal 20-yr term from priority
A61K 31/381A61K 31/423A61K 31/505A61K 31/433A61K 31/513A61K 31/12A61K 31/35A61K 31/426A61K 31/4365A61K 31/427A61K 31/4196A61K 31/437A61K 31/428A61K 31/4245A61K 31/39A61K 31/50A61K 31/27A61K 31/422A61K 31/18C07D 311/76A61K 31/4164
40
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Claims
Abstract
Provided are compounds which are Spt5 inhibitors and which are for use in the treatment diseases and disorders in which inhibiting one or more activities of Spt5 is beneficial, such as, for example, Trinucleotide repeat disorders, obesity, inflammatory diseases, infectious diseases and cancer. The compounds are represented by Formulae I-VII, as defined in the specification.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating a nucleotide repeat disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by Formula Ia:
wherein:
n and m are each independently an integer of from 0 to 4;
R 1 and R 2 are each independently a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, thiol, alkoxy, thioalkoxy, aryloxy, thioaryloxy, halo, alkyl, amine, amide, nitro, carboxylate and thiocarboxylate;
B is a cyclic moiety selected from aryl, heteroaryl and heteroalicyclic; and
L is a linking moiety, comprising from 2 to 12 atoms in length, and comprising a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain, interrupted by or comprising one or more of S and —S(═O) 2 thereby treating a nucleotide repeat disorder in the subject.
2 . The method of claim 1 , wherein B is a heteroaryl or a heteroalicyclic.
3 . The method of claim 2 , wherein L is a substituted, saturated hydrocarbon interrupted by at least one S, and optionally further interrupted by O.
4 . The compound for use of claim 2 , wherein L is an unsaturated hydrocarbon which comprises and aryl and SO 2 , and optionally
further comprises —NR 4 —, wherein R 4 is hydrogen, alkyl, cycloalkyl or aryl.
5 . The method of claim 1 , wherein B is aryl.
6 . The method of claim 1 , wherein the compound inhibits binding of Spt5 to Pol II or changes the conformation of a Spt5-Pol II complex.
7 . A method of treating a nucleotide repeat disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by Formula VII:
wherein:
n and m and w are each independently an integer of from 0 to 4;
R 1 and R 2 are each independently a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, hydroxyalkyl, thiol, alkoxy, thioalkoxy, aryloxy, thioaryloxy, halo, alkyl, amine, amide, nitro, carboxylate and thiocarboxylate;
A and B are each independently a cyclic moiety selected from aryl, heteroaryl and heteroalicyclic;
L is a linking moiety, comprising from 2 to 12 atoms in length, and comprising a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain, interrupted by or comprising one or more of O, S and —S(═O) 2 ,
thereby treating the nucleotide repeat disorder in the subject.
8 . The method of claim 7 , wherein L is an unsaturated, substituted hydrocarbon chain interrupted by O or S.
9 . The method of claim 7 , wherein at least one of n and m is other than 0 and at least one of R 1 and R 2 if present is a hydroxyalkyl.
10 . The method of claim 7 , wherein B is a heteroaryl or a heteroalicyclic.
11 . The method of claim 7 , wherein A is a heteroaryl or a heteroalicyclic.
12 . The method of claim 7 , wherein B is aryl.
13 . The method of claim 7 , wherein said compound inhibits binding of Spt5 to Pol II or changes the conformation of a Spt5-Pol II complex.
14 . A method of treating a nucleotide repeat disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the group of compounds presented in Tables 6, 7, 8 and 9, thereby treating the nucleotide repeat disorder in the subject.
15 . The method of claim 14 , wherein said compound inhibits binding of Spt5 to Pol II or changes the conformation of a Spt5-Pol II complex.
16 . A method of treating a nucleotide repeat disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from:
a compound represented by Formula I:
wherein:
n and m and w are each independently an integer of from 0 to 4;
R 1 and R 2 are each independently a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, thiol, alkoxy, thioalkoxy, aryloxy, thioaryloxy, halo, alkyl, amine, amide, nitro, carboxylate and thiocarboxylate;
B is a cyclic moiety selected from aryl, heteroaryl and heteroalicyclic;
L is a linking moiety, comprising from 2 to 12 atoms in length, and comprising a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain, optionally interrupted by one or more of O, S, —S(═O)—, —S(═O) 2 and —NR 4 —, wherein R 4 is hydrogen, alkyl, cycloalkyl or aryl,
and
a compound represented by Formula II:
wherein:
w is an integer of from 0 to 4;
R 3 is a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, thiol, alkoxy, thioalkoxy, aryloxy, thioaryloxy, halo, alkyl, amine, amide, nitro, carboxylate and thiocarboxylate;
X 1 and X 2 are each independently O, S or NR 4 ;
Y is —C(═X 3 )—or —CR 5 R 6 —C(═X 3 )-, wherein X 3 is O, S or NR 4 ,
wherein R 4 is hydrogen, alkyl, cycloalkyl or aryl,
and R 5 and R 6 are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, thiol, alkoxy, thioalkoxy, aryloxy, thioaryloxy, halo, alkyl, amine, amide, nitro, carboxylate and thiocarboxylate, or, alternatively, two or more of R 4 , R 5 and R 6 from together a cyclic moiety,
thereby treating the nucleotide repeat disorder in the subject.
17 . The method of claim 16 , wherein said compound inhibits binding of Spt5 to Pol II or changes the conformation of a Spt5-Pol II complex.
18 . The method of claim 16 , wherein the compound is represented by Formula II, and wherein X 1 and X 2 are each independently O or S.
19 . The method of claim 18 , wherein Y is C═X 3 .
20 . The method of claim 16 , wherein the compound is represented by Formula I, and wherein B is aryl.
21 . The method of claim 20 , wherein L is or comprises an unsaturated hydrocarbon chain substituted by one or more oxo (═O) groups.
22 . The method of claim 16 , wherein the compound is represented by Formula I, and wherein B is a heteroaryl or a heteroalicyclic.
23 . The method of claim 22 , wherein L is:
a hydrocarbon interrupted by one or two —NR 4 —, being optionally substituted and/or unsaturated; or a saturated unsubstituted hydrocarbon interrupted by —NR 4 —, and m is 1; or a substituted, saturated or unsaturated, hydrocarbon interrupted at least by S or S(═O) 2 .
24 . A method of inducing suppression of appetite and/or in treating obesity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from a compound represented by Formula III:
wherein:
k is an integer of from 0 to 8;
Each of R 10 , if present, is selected from alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, thioalkoxy and thioaryloxy; and
X 4 , X 5 and X 6 are each independently selected from O, S and NR 4 , wherein R 4 is hydrogen, alkyl, cycloalkyl or aryl,
thereby inducing suppression of appetite and/or treating obesity in the subject.Join the waitlist — get patent alerts
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